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Title: | Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment |
Author: | Martínez González, Loreto Rodríguez Cueto, Carmen Cabezudo, Diego Bartolomé, Fernando Andrés Benito, Pol Ferrer, Isidro (Ferrer Abizanda) Gil, Carmen Martín Requero, Ángeles Fernández Ruiz, Javier Martínez, Ana Lago, Eva de |
Keywords: | Esclerosi lateral amiotròfica Proteïnes quinases Amyotrophic lateral sclerosis Protein kinases |
Issue Date: | 10-Mar-2020 |
Publisher: | Nature Publishing Group |
Abstract: | athogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease where no treatment exists, involves the compartmentalization of the nuclear protein TDP-43 (TAR DNA-binding protein 43) in the cytoplasm which is promoted by its aberrant phosphorylation and others posttranslational modifications. Recently, it was reported that CK-1δ (protein casein kinase-1δ) is able to phosphorylate TDP-43. Here, the preclinical efficacy of a benzothiazole-based CK-1δ inhibitor IGS-2.7, both in a TDP-43 (A315T) transgenic mouse and in a human cell-based model of ALS, is shown. Treatment with IGS-2.7 produces a significant preservation of motor neurons in the anterior horn at lumbar level, a decrease in both astroglial and microglial reactivity in this area, and in TDP-43 phosphorylation in spinal cord samples. Furthermore, the recovery of TDP-43 homeostasis (phosphorylation and localization) in a human-based cell model from ALS patients after treatment with IGS-2.7 is also reported. Moreover, we have shown a trend to increase in CK-1δ mRNA in spinal cord and significantly in frontal cortex of sALS cases. All these data show for the first time the in vivo modulation of TDP-43 toxicity by CK-1δ inhibition with IGS-2.7, which may explain the benefits in the preservation of spinal motor neurons and point to the relevance of CK-1δ inhibitors in a future disease-modifying treatment for ALS. |
Note: | Reproducció del document publicat a: https://doi.org/10.1038/s41598-020-61265-y |
It is part of: | Scientific Reports, 2020, vol. 10, p. 4449 |
URI: | http://hdl.handle.net/2445/171935 |
Related resource: | https://doi.org/10.1038/s41598-020-61265-y |
ISSN: | 2045-2322 |
Appears in Collections: | Articles publicats en revistes (Patologia i Terapèutica Experimental) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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